Process for the isomerisation of a cyclohexenyl alkyl or alkenyl ketone

ABSTRACT

The present invention relates to a process for the carbon-carbon double bond isomerisation of a 2-alkyl-cyclohex-3-enyl alkyl or alkenyl ketone into a mixture comprising the corresponding 2-alkyl-cyclohex-2-enyl ketones and the corresponding 2-alkylene-cyclohexyl ketones, using as catalyst a ruthenium complex obtainable by the reaction of an appropriate ruthenium organometallic precursor and an acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International applicationPCT/IB2004/003978 filed Nov. 30, 2004, the entire content of which isexpressly incorporated herein by reference thereto.

TECHNICAL FIELD

The present invention relates to the field of organic synthesis. Moreparticularly it provides a process for the isomerisation of a2-alkyl-cyclohex-3-enyl alkyl or alkenyl ketone into a mixturecomprising the corresponding 2-alkyl-cyclohex-2-enyl ketones and thecorresponding 2-alkylene-cyclohexyl ketones, using as catalyst a complexobtainable by the reaction of an appropriate ruthenium organometallicprecursor and an acid.

BACKGROUND

The compounds of formula (II) or (II′), as defined below, can be usefulas perfuming ingredients or as starting material for the construction ofcompounds having a more complex skeleton.

The methods of preparation of said compounds reported in the prior artare in general quite long and expensive. Moreover, each of said methodsallows to obtain only one or the other of said compounds. Consequently,to obtain said compounds a person skilled in the art has to carry outtwo separate processes with an evident loss of time.

It is therefore highly desirable to access such compounds by means of asimple and efficient isomerisation process wherein the starting materialis an easily accessible material and it is possible to obtain bothcompounds (II) and (II′).

To the best of our knowledge, in the prior art there is no report of anisomerisation process giving a direct access to compounds of formulae(II) and (II′) at the same time.

SUMMARY OF THE INVENTION

The present invention now relates to a process for the summarization ofa 2-alkyl-cyclohex-3-enyl alkyl or alkenyl ketone into a mixturecomprising the corresponding 2-alkyl-cyclohex-2-enyl ketones and thecorresponding 2-alkylene-cyclohexyl ketones, using as catalyst a complexobtainable by the reaction of an appropriate ruthenium organometallicprecursor and an acid. The process can be also used to obtain opticallyactive compounds. The invention also relates about the catalysts.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In order to solve the problems aforementioned, the present inventionprovides a process for the isomerisation of a substrate of formula

wherein each R¹ represents, simultaneously or independently, a hydrogenatom or a methyl group and R² represents a hydrogen atom linear orbranched C₁₋₄ alkyl or a C₂₋₅ 1-alkenyl group;into a mixture comprising at least one compound of formula (II) and atleast one compound of formula (II′)

wherein R¹ and R² have the same meaning as indicated above;said process being carried out in a non-coordinating or weaklycoordinating medium, under an inert atmosphere and in the presence of acatalyst obtainable by the reaction of

-   a) a ruthenium precursor of the formula [Ru(diene)(allyl)₂],    [Ru(dienyl)₂], [Ru(tetraene)(ene)] or [Ru(diene)(triene)]; and-   b) a protic acid of formula HX, wherein X is a weakly- or    non-coordinating anion; or a Lewis acid of formula B(R³)₃, wherein    R³ represents a fluoride or a phenyl group optionally substituted by    one to five groups such as halide atoms or methyl or CF₃ groups, or    a Lewis acid of formula FeX₃, FeX₂, AgX, AlY₃, FeY₃, FeY₂, SnY₂,    SnY₄, AgY, AgY₂, SbY₅, AsY₅ or PY₅, X being a group as defined above    and Y being a fluorine or chlorine atom;    in a non-coordinating or weakly coordinating medium and under an    inert atmosphere, the molar ratio acid/ruthenium being comprised    between 0.3 and 3.1.

Another compound which may be present in the mixture obtained by theinvention's isomerisation process, and which is useful to be mentioned,is an enone of formula

wherein R¹ and R² have the same meaning as indicated in formula (I).Said compound (III) is an optional constituent of the mixture obtainedat the end of the isomerisation. In fact, the applicant has observedthat the formation of said compound (III) depends on the specificexperimental conditions, in particular on ratio Ru/acid, on thetemperature and the duration of the reaction, or on the catalyst usedand its concentration. In general, the compound (III) accounts for lessthan 2% of the weight of the final mixture. According to a preferredembodiment of the invention, the final mixture is devoid of saidcompound of formula (III).

According to a preferred embodiment of the invention the substrate is acompound of formula

wherein R¹ and R² have the same meaning as indicated in formula (I),preferably R¹ representing a hydrogen atom and R² representing ahydrogen atom or a methyl or CH═CHCH₃ group; andthe mixture obtained comprises the corresponding compounds of formulae(V) and (V′)

wherein R¹ and R² have the same meaning as indicated for formula (IV).

In this embodiment, the optional ingredient, mentioned above, of themixture would be of the formula

wherein R¹ and R² have the same meaning as indicated for formula (VI).

Furthermore, it is also important to mention, regardless of the specificembodiments, than compounds of formula (I), as well as the correspondingcompounds (II) or (II′), can be in an optically active form. Inparticular, compounds (I), (II) or (II′) can be of formula

wherein R¹ and R² have the same meaning as indicated above and theasterisk means that said compounds are in an optically active form.

Specific examples of compound (I) optically active are(2E)-1-[(1S,2R)-2,6,6-trimethyl-3-cyclohexen-1-yl]-2-buten-1-one,(2E)-1-[(1S,2S)-2,6,6-trimethyl-3-cyclohexen-1-yl]-2-buten-1-one,1-[(1S,2R)-2,6,6-trimethyl-3-cyclohexen-1-yl]-1-ethanone or1-[(1S,2S)-2,6,6-trimethyl-3-cyclohexen-1-yl]-1-ethanone.

The catalyst is an essential element of the invention's process. Asmentioned above said catalyst is obtainable by the reaction of anorganometallic ruthenium precursor and a particular Lewis or protic acidin a non-coordinating or weakly coordinating medium and under an inertatmosphere.

As non-limiting examples of suitable ruthenium precursors one can citecompounds of general formula [Ru(diene)(allyl)₂] wherein “diene” standsfor a C₄-C₂₀, preferably C₄-C₁₀, hydrocarbon group comprising twocarbon-carbon double bonds, such as for example COD(cycloocta-1,5-diene) or NBD (norbornadiene), or yet hepta-1,4-diene,and “allyl” stands for a C₃-C₂₀, preferably C₃-C₁₀, hydrocarbon groupcomprising a fragment C═C—C⁻, or C═C—C*, such as for example 2-allyl or2-methallyl (see, for instance, J. P. Genet et al., cited references; M.O. Albers et al., Inorganic Synth., 1989, 26, 249; R. R. Schrock et al.,J. Chem. Soc. Dalton Trans., 1974, 951).

Other appropriate ruthenium complexes include the compounds of the[Ru(dienyl)₂] type, wherein “dienyl” stands for a C₄-C₂₀, preferablyC₄-C₁₅, hydrocarbon group comprising a carbon-carbon double bond and afragment C═C—C⁻, C═C—C* or C═C—O⁻, such for example the pentadienyl,cyclopentadienyl, a substituted cyclopentadienyl (such aspentamethyl-cyclopentadienyl), 2,4-dimethylpentadienyl,2,3,4-trimethylpentadienyl, 2,4-di(tert-butyl)-pentadienyl or yet2,4-dimethyl-1-oxapentadienyl (see, for example, R. D. Ernst et al., J.Organometallic Chem., 1991, 402, 17; L. Stahl et al., Organometallic1983, 2, 1229; T. Schmidt et al., J. Chem. Soc. Chem. Commun., 1991,1427; T. D. Newbound et al., Organometallics, 1990, 9, 2962), or yet2,5-cyclooctadienyl or 2,5-cycloheptadienyl (see, for example, P.Pertici et al., J. Chem. Soc. Dalton Trans., 1980, 1961).

Yet other appropriate ruthenium complexes are of formula[Ru(diene)(triene)], wherein “triene” stands for a C₇-C₂₀, preferablyC₇-C₁₂, hydrocarbon group comprising three carbon-carbon double bonds,such as for example cycloocta-1,3,5-triene (COT), benzene or asubstituted benzene such as a hexa-methyl-benzene. The preferred trineis COT.

Another appropriate ruthenium complex is of formula [Ru(tetraene)(ene)],wherein “tetraene” stands for a C₈-C₂₀, preferably C₈-C₁₂, hydrocarbongroup comprising four carbon-carbon double bonds, such as for examplecycloocta-1,3,5,7-tetraene, and “ene” stands for a C₂−C₁₀, preferablyC₄−C₈, hydrocarbon group comprising one carbon-carbon double bond, suchas for example cyclooctene or cyclohexene.

Following a preferred embodiment of the invention, there is used as theRu precursor, the compound of formula [Ru(COD)(2-methallyl)₂],[Ru(COD)(COT)], [Ru(2,4-dimethylpentadienyl)₂] (e.g. L. Stahl et al. orT. D. Newbound et al., references cited) or the[Ru(2,4-dimethyl-1-oxapentadienyl)₂] complexes (e.g. T. Schmidt et al.,reference cited). [Ru(COD)(2-methallyl)₂], the preparation of which wasfirst reported by J. Powell et al., in J. Chem. Soc., (A), 1968, 159,proved quite convenient from a practical point of view.

In the process for the preparation of the catalyst there is used anacid, said acid is believed to cationize the ruthenium precursor.

A first type of suitable acids employed in the preparation of thecatalyst is of the protic type. Said protic acid must have a weakly- ornon-coordinating anion. By the expression “weakly- or non-coordinatinganion” we mean here an anion which does not interact significantly,under the reaction conditions, with the catalyst, such a notion is wellunderstood by a person skilled in the art of the catalysis. In otherwords, a weakly- or non-coordinating anion is an anion which does notcoordinate at all the Ru center of the catalyst or which has acoordination stability constant inferior to that of the substrate offormula (I).

Non-limiting examples of protic acids suitable for the preparation ofthe catalyst are acid of formula HX, wherein X is a ClO₄ ⁻, R⁴SO₃ ⁻,wherein R⁴ is a chlorine of fluoride atom or a C₁-C₈ fluoroalkyl orfluoroaryl group, BF₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsCl₆ ⁻, SbF₆ ⁻, AsF₆ ⁻ or BR₄⁻, wherein R is a phenyl group optionally substituted by one to fivegroups such as halide atoms or methyl or CF₃ groups.

According to a preferred embodiment of the invention, the weakly- ornon-coordinating anion is BF₄ ⁻, PF₆ ⁻, C₆F₅SO₃ ⁻, CF₃SO₃ ⁻ or yetB[3,5-(CF₃)₂C₆H₄]₄ ⁻, even more preferably BF₄ ⁻.

Such protic acids can be used in the form of the corresponding etherates(for example HBF₄R⁵ ₂O, R⁵ being a C₁-C₅ hydrocarbon group such as C₂H₅or C₄H₉). These etherates are commercial products, or they can beprepared by reacting AgX with HCl in a solvent containing adialkylether, for example a mixture of dichloromethane and diethylether.As the silver chloride precipitates, it provides the etherate solutionof the acid, which can then be used according to the invention in thereaction with the ruthenium precursor.

A second type of suitable acid employed in the preparation of thecatalyst is of the Lewis type. Suitable examples of such acids areFeCl₃, AlCl₃, SbF₅, AsF₅ or PF₅, AgF, Fe(CF₃SO₃)₃, AgBF₄, SnCl₂, BF₃ orBMe₃.

These acids can be in an anhydrous form or, for some of them, also in ahydrate form. Furthermore, the boron or aluminum derivative, especiallyBF₃, could be in the form of anyone of its adduct with an ether orcarboxylic acid, such as R⁶ ₂O or R⁷COOH, wherein R⁶ is a C₁-C₅ alkylgroup and R⁷ is a C₁-C₂₀ alkyl group. According to a particularembodiment of the invention, preferred Lewis acid is BF₃ or a BF₃ adductwith Et₂O, Bu₂O or AcOH.

According to the above, in the preparation of the catalyst, the acid andthe Ru precursor are reacted in a molar ratio comprised between 0.3 and3.1. According to a preferred embodiment of the invention said ratio iscomprised between approximately 0.5 and 2.

In order not to compromise its effectiveness, the catalyst should alsobe prepared in a non-coordinating or weakly coordinating solvent andunder an inert atmosphere. By the expression “non-coordinating or weaklycoordinating solvent” we mean here a solvent which does not deactivatesignificantly the catalyst and allows the substrate to interact with thecatalyst, such a notion is well understood by a person skilled in theart of the catalysis. In other words, a weakly- or non-coordinatingsolvent is a solvent which does not coordinate at all the Ru center ofthe catalyst or which has a coordination stability constant inferior tothat of the substrate of formula (I).

In general, any solvent which is inert under the experimental conditionsand is able to solubilize the substrate and catalyst is particularlyappreciated. In a particular embodiment of the invention, such a solventis a chlorinated hydrocarbon, saturated or unsaturated hydrocarbon, anether, an ester, a carboxylic acid, a weakly coordinating ketone(sterically hindered ketone) or a substrate of formula (I) or a mixturethereof. Specific examples of such solvents are CH₂Cl₂, heptane, octane,dibutylether, butylacetate, acetic acid, teramyl methylether,diisopropylketone or yet a compound of formula (IV) as defined above.

By the expression “inert atmosphere” we mean here an atmosphere which isnot reactive towards the catalyst, and in particular an atmosphere whoseoxygen content is lower than 200 ppm, and preferably not above 100 ppm.

To the best of our knowledge, the catalysts obtained according to aprocess described above and wherein the acid is a Lewis acid, as definedabove, are new compounds. Said catalysts are also an object of thepresent invention. Preferred Lewis acid are BF₃, BF₃.Et₂O, BF₃. Bu₂O orBF₃.(AcOH)₂. Preferred ruthenium precursor are the complexes[Ru(COD)(2-methallyl)₂], [Ru(COD)(COT)], [Ru(2,4-dimethylpentadienyl)₂]or [Ru(2,4-dimethyl-1-oxapentadienyl)₂], and in particular[Ru(COD)(2-methallyl)₂].

The invention's process should also be carried out in a non-coordinatingor weakly coordinating solvent and under an inert atmosphere. Saidsolvent and atmosphere are defined as above for the formation of thecatalyst.

The amount in which the catalyst may be employed in the invention'sprocess is typically comprised between 0.01 and 2 molar %, relative tothe substrate. In a preferred embodiment of the process of the inventionthe catalyst is used in a concentration comprised between about 0.05 and1 molar %. More preferably, the amount of the catalyst can be comprisedbetween approximately 0.1 and 0.4 molar %. The use of high amounts ofcatalyst may lend to the presence of the compound of formula (III) inthe obtained mixture.

The temperature at which the process of the invention can be carried outis comprised between 60° C. and the refluxing temperature of the solventor of the substrate. Preferably, the temperature is in the range ofbetween 60° C. and 180° C., more preferably between 110° C. and 165° C.,and even more preferably between 110° and 150° C. Of course, a personskilled in the art is also able to select the preferred temperature as afunction of the melting and boiling point of the starting and finalproducts as well as of the solvent.

However it has to be said that when the process temperature is in therange comprised between 150° and 180° C. the mixture obtained at the endof the process may contain an appreciable amount of compound of formula(III), especially if the reaction is left at such temperature even afterthe conversion of the substrate is no longer observed.

EXAMPLES

The invention will now be described in further detail by way of thefollowing examples, wherein the abbreviations have the usual meaning inthe art, the temperatures are indicated in degrees centigrade (° C.).

Example 1 Summarization of1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone in the presence of acatalyst obtained using a protic acid

To trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone (4.52 mol;trans/cis=94/5 to 99/1, purity≧99%) stirred under nitrogen at 20° C. wasadded HBF₄.OEt₂ (4.54 mmol of HBF₄) and [Ru(COD)(methallyl)₂] (4.54mmol) was added consecutively. The resulting solution was heated to 130°C. and stirred over 30 minutes at 130° C. under nitrogen. Afterwards,the resulting mixture was cooled to 20° C. and there was obtained amixture comprising (% by weight of the final mixture, obtained by GCanalysis):

trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone 6% cis1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone 1%1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethanone 86%1-(2,2-dimethyl-6-methyene-1-cyclohexyl)-1-ethanone 2%1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethanone 2%

Example 2 Isomerisation of1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone in the presence of acatalyst obtained using a Lewis acid

To trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone (4.52 mol;trans/cis=94/5 to 99/1, purity≧99%) stirred under nitrogen at 20° C. wasadded BF₃.(AcOH)₂ (2.27 mmol of BF₃) and [Ru(COD)(methallyl)₂] (2.27mmol) was added consecutively. The resulting solution was heated to 130°C. and stirred over 30 minutes at 130° C. under nitrogen. Afterwards,the resulting mixture was cooled to 20° C. and there was obtained amixture comprising (% by weight of the final mixture, obtained by GCanalysis):

trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone 7% cis1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone 1%1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethanone 87%1-(2,2-dimethyl-6-methyene-1-cyclohexyl)-1-ethanone 2%1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethanone not observed

Example 3 Summarization of1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-buten-1-one in the presence of acatalyst obtained using a Lewis acid

To trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-buten-1-one (25 g; 130mmol; trans:cis 98:2; purity≧99%) stirred under nitrogen at 20° C. wasadded BF₃.(AcOH)₂ (0.65 mmol) and [Ru(COD)(methallyl)₂] (0.65 mmol) areadded consecutively. The resulting solution was heated to 130° C. andstirred over 60 minutes at 130° C. under nitrogen. Then the resultingmixture is cooled to 20° C. and there was obtained a mixture comprising(% by weight of the final mixture, obtained by GC analysis):

trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-buten-1-one 9%1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one 86%1-(2,2-dimethyl-6-methyene-1-cyclohexyl)-2-buten-1-one 1%1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one not observed

1. A process for the isomerisation of a substrate of formula

wherein each R¹ represents, simultaneously or independently, a hydrogenatom or a methyl group and R² represents a hydrogen atom linear orbranched C₁₋₄ alkyl or a C₂₋₅ 1-alkenyl group; into a mixture comprisingat least one compound of formula (II) and at least one compound offormula (II′)

wherein R¹ R² have the same meaning as indicated above; said processbeing carried out in a non-coordinating or weakly coordinating medium,under an inert atmosphere and in the presence of a catalyst obtained bythe reaction of a) a ruthenium precursor of the formula[Ru(diene)(allyl)₂], [Ru(dienyl)₂], [Ru(tetraene)(ene)] or[Ru(diene)(triene)]; and b) a protic acid of formula HX, wherein X is aweakly-or non-coordinating anion; or a Lewis acid of formula B(R³)₃,wherein R³ represents a fluoride or a phenyl group optionallysubstituted by one to five groups such as halide atoms or methyl or CF₃groups, or a Lewis acid of formula FeX₃, FeX₂, AgX, AlY₃, FeY₃, FeY₂,SnY₂, SnY₄, AgY, AgY₂, SbY₅, AsY₅ or PY₅, X being a group as definedabove arid Y being a fluorine or chlorine atom; in a non-coordinating orweakly coordinating medium and under an inert atmosphere, the molarratio acid/ruthenium being comprised between 0.3 and 3.1.
 2. A processaccording to claim 1, wherein compounds (I), (II) or (II′) are offormula

wherein R¹ and R² have the same meaning as in claim 1 and the asteriskmeans that said compounds are in an optically active form.
 3. A processaccording to claim 1, wherein the substrate is of formula

wherein R¹ and R² have the same meaning as indicated in claim 1; and themixture obtained comprises the corresponding compounds of formulae (V)and (V′)

wherein R¹ and R² have the same meaning as indicated in claim
 1. 4. Aprocess according to claim 3, wherein R¹ represents a hydrogen atom andR² represents a hydrogen atom or a methyl or CH═CHCH₃ group.
 5. Aprocess according to claim 1, wherein the ruthenium precursor is acompounds of general formula i) [Ru(diene)(allyl)₂] wherein “diene”stands for COD (cycloocta-1,5-diene), NBD (norbornadiene) orhepta-1,4-diene, and “allyl” stands for 2-allyl or 2-methallyl; ii)[Ru(dienyl)₂] wherein “dienyl” stands for pentadienyl,2,4-dimethylpentadienyl, 2,3,4-trimethylpentadienyl,2,4-di(tert-butyl)-pentadienyl, 2,4-dimethyl-1-oxapentadienyl or2,5-cyclooctadienyl or 2,5-cycloheptadienyl; iii) [Ru(diene)(triene)]wherein “diene” has the same meaning as above and “triene” stands forcycloocta-1,3,5-triene (COT); or iv) [Ru(tetraene)(ene)], wherein“tetraene” stands for cycloocta-1,3,5,7-tetraene and “ene” stand forcyclooctene or cyclohexene.
 6. A process according to claim 1, wherein Xis a CIO₄ ⁻, R⁴SO₃ ⁻, wherein R⁴ is a chlorine of fluoride atom or anC₁-C₈ fluoroalkyl or fluoroaryl group, BF₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsCl₆ ⁻,SbF₆ ⁻, AsF₆ ⁻ or BR₄ ⁻, wherein R is a phenyl group optionallysubstituted by one to five groups such as halide atoms or methyl or CF₃groups.
 7. A process according to claim 1, wherein the acid HX isHBF₄Et₂O.
 8. A process according to claim 1, wherein the Lewis acid isFeCl₃, AlCl₃, SbF₅, AsF₅ or PF₅, AgF, Fe(CF₃SO₃)₃, AgBF₄, SnCl₂, BF₃,BMe3 or an add of BF₃ with an ether or carboxylic acid R⁶ ₂O or R⁷COOH,wherein R⁶ is a C₁-C₅ alkyl group and R⁷ is a C₁-C₂₀ alkyl group.
 9. Acatalyst obtained by the reaction of a) a ruthenium precursor of theformula [Ru(diene)(allyl)₂], [Ru(dienyl)₂], [Ru(tetraene)(ene)] or[Ru(diene)(triene)]; and b) a Lewis acid of formula B(R³)₃, wherein R³represents a fluoride or a phenyl group optionally substituted by one tofive groups such as halide atoms or methyl or CF₃ groups, or a Lewisacid of formula FeX₃, FeX₂, AgX, AlY₃, FeY₃, FeY₂, SnY₂, SnY₄, AgY,AgY₂, SbY₅, AsY₅ or PY₅, X being a group as defined above and Y being afluorine or chlorine atom; the molar ratio acid/ruthenium beingcomprised between 0.3 and 3.1 and the reaction being carried out in anon-coordinating or weakly coordinating medium and under an inertatmosphere.
 10. A catalyst according to claim 9, wherein the Lewis acidis BE₃, BF₃.Et₂O, BF₃.Bu₂O or BF₃.(AcOH)₂.